Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is now widely acknowledged to be essential for the development of Kaposi's sarcoma (KS), an endothelial proliferation that is the leading neoplasm of AIDS patients. The majority of KS cases occur as a consequence of the combination of immunosuppression and KSHV infection, as seen in both AIDS-related cases and in transplant patients. The initial presentation of KS in HIV-infected individuals often occurs in the mouth, with oral cavity involvement in the majority of AIDS patients who develop the neoplasm. Thus, KS is the most common intraoral malignancy seen in HIV-infected individuals. In the HIV co-infected host, KSHV is frequently carried in the oral mucosa and the virus is actively shed into the saliva. The oral mucosal fluid is the only source of infectious, transmissible KSHV isolated directly from infected patients that has been identified to date. Recent evidence suggests that oral epithelial keratinocytes undergoing lytic replication of KSHV are the primary source of infectious virus in vivo. Furthermore, in latently-infected keratinocytes, KSHV has been shown to be activated and switch from a latent state to a lytically replicating state with production of infectious virus as the keratinocytes undergo their normal pathway of differentiation. These studies suggest that the environment of the oral cavity plays an important role in the transmission and pathogenesis of KSHV. Despite compelling evidence, identification of the mechanism and the location of KSHV pathogenesis in the oral mucosa of AIDS patients has remained elusive. The majority of KSHV research has targeted cells of endothelial and lymphocyte origin, due to the role of KSHV in tumor development in these cell types. This project has as a long term goal the elucidation of the role of the oral environment in the biology and pathogenesis of KSHV. We propose to further develop a novel system for studying primary lytic and latent infections in the oral epithelial keratinocytes. We will also identify and characterize the viral and cellular factors involved in KSHV entry and infection of these cells. In particular, we will identify the constituents of the virion envelope of KSHV produced by oral epithelial cells that are responsible for virus binding and entry, and determine the cellular receptors in these cells that mediate entry and infection. These studies will help us to develop a more complete understanding of the cellular interactions required for KSHV infection of the oral epithelium with important implications regarding the development of new antiviral and anti-tumor approaches.